The present invention relates to anticancer treatment using compounds which are water-soluble prodrugs of triptolide or its derivatives.
Although many cancers can be cured by surgical resection, chemotherapy is often used as an adjunct to surgical therapy, and is used primarily in the treatment of nonoperable or metastatic malignancy.
Colorectal cancer is a disease that kills nearly half of those afflicted within 5 years of initial diagnosis, and approximately one in 17 Americans develop colorectal cancer during their lifetime. Surgical intervention is not an option for most patients with advanced metastatic colorectal cancer. Initial chemotherapy with fluorouracil (5-FU) and leucovorin has become the standard for patients with stage III colon cancer (NIH Consensus Conference, xe2x80x9cAdjuvant therapy for patients with colon and rectal cancerxe2x80x9d, JAMA 264: 1444-1450, 1990; Goldberg R M and Erlichman C, Oncology 12: 59-63, 1998). Irinotecan is currently used to treat patients with 5-FU-refractory advanced colorectal cancer (Van Cutsem E and Blijham G H, Semin Oncol 26: 13-20, 1999; Cunningham D et al., Lancet 352: 1413-1418, 1998).
Breast cancer is the second most common form of cancer among women in the U.S., and the second leading cause of cancer deaths among women. In treatment of breast cancer, adjuvant systemic therapy is begun soon after primary therapy (surgery and radiation therapy) to delay recurrence and/or to prolong survival. Current treatment regimens include a combination regimen of cyclophosphamide, methotrexate and 5-fluorouracil (CMF), as well as the anthracyclines, doxorubicin (adriamycin) and epirubicin, and, for treatment of advanced and metastatic cancers, the taxanes, paclitaxel (Taxol) and docetaxel (Taxotere).
Prostate cancer is the most common cancer in men, with an estimated 244,000 cases in 1995 in the United States. It is the second leading cause among men who die from neoplasia, with an estimated 44,000 deaths per year. Prostate cancer has been found to be relatively resistant to conventional cytotoxic chemotherapy, and toxicity can make such therapy unsuitable for elderly patients. Where prostate cancer is localized, detected early, and the patient""s life expectancy is 10 years or more, radical prostatectomy offers the best chance for eradication of the disease; however, patients with bulky, high-grade tumors, or who are older or less healthy, are less likely to be successfully treated by radical prostatectomy. Radiation therapy may be used as an alternative, but long-term recurrence of the disease is a problem.
In view of the high number of deaths each year resulting from cancer, a continuing need exists to identify effective and relatively nontoxic chemotherapeutic drugs for use as anticancer agents.
In one aspect, the invention provides a method of anticancer treatment. The method comprises administering to a subject in need of such treatment, an effective amount of a triptolide prodrug, as represented by any of structures I-IV, as shown and described below, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable vehicle. Preferred compounds are those of structure I; a particularly preferred compound is triptolide 14-succinate, designated herein as PG490-88. In preferred embodiments, the method is used for treatment of cancer or tumors of the colon, lung, breast, or prostate. The invention also provides pharmaceutical compositions for anticancer or antitumor treatment, consisting essentially of a triptolide prodrug as represented by any one of structures I-IV, as shown and described below, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable vehicle. The compositions are employed in anticancer treatment methods as described herein.
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.